The present invention concerns novel uses of dl-tetrahydropalmatine (dl-THP) and its related compounds, methods of treatment of patients in need of same, and methods of manufacture of medicaments for treatment of patients, and the use of dl-THP in same.
dl-THP (also known as Corydalis B, full name 5,8,18,13a-tetrahydro-2,3,9,10-tetramethoxy-6H-dibenzo [a,q] quinolizine) is a well known compound which has in the past been shown to have a number of therapeutic effects. Reference herein to xe2x80x9ctherapyxe2x80x9d in its various forms is to any treatment which is designed to cure, alleviate, remove or lessen the symptoms of, or prevent or reduce the possibility of contracting any disorder or malfunction of the human or animal body. U.S. Pat. No. 5,242,926 claims the treatment of hyperthyroidism using dl-THP. U.S. Pat. No. 5,308,619 claims the use of the active ingredient extracts of Corydalis and Eschscholtzia in treating states of agitation and nervous dysfinction. U.S. Pat. No. 5,547,956 discloses its use in methods for treating drug addicts"" withdrawal symptoms. It is readily isolated from e.g. Corydalis yanhusuo W. T. Wang, a traditional Chinese medicine of which it is just one of the active ingredients, the plant being used for promoting blood circulation, reinforcing vital energy and alleviating pain. Corydalis yanhusuo can also palliate the stagnation of vital energy or blood stasis, which would otherwise result in headache, chest pain, hypochondriac pain, epigastric pain, abdominal pain, backache, arthralgia, dysmenofrhea or trauma dl-THP has been shown to deplete the levels of dopamine, noradrenaline and serotonin in the CNS (Liu G Q et al., Arch Int Pharmacodyn Ther July 1982;258(1):39-50; PMID 6182845), and to decrease both arterial pressure and heart rate through a serotonergic release process in the hypothalamus (Chueh F Y et al., Jpn J Pharmacol. October 1995;69(2): 177-80; PMID: 8569056). It also decreases motor activity. It is also known to be protective in rat heatstrokes (Chang C K et al., Neurosci Lett. May 28, 1999;267(2): 109-12; PMID: 10400224). Targets in the CNS for the two enantiomers (i.e. the d and l enantiomers) of dl-THP have been identified and therapeutic effects shown, including causing a sedative-tranquilizing effect and inhibiting voltage-dependent Ca2+ channels (Vauquelin et al., Neurochemistry International, 1989 15(3):321-324).
dl-THP is widely available and is sold as being a herbal dietary supplement and as a sleeping pill.
A pharmacological study of dl-THP (Hsu B et al., Archives Internationales de Phannacodynamie 1962; CXXXIX: 318-327) on lab animals has shown it to have an analgesic effect. It has a sedative-tranquilizing action, decreases the toxicity of amphetamine, prevents abnormal activity cause by mescaline, causes an extinction of conditioned avoidance responses, and causes calning with marked sedation. Clinical trials in hospitals have shown in cases of dull visceral pain a marked analgesic effect for dl-THP, and that it is useful as a short acting hypnotic in patients with insomnia. Additional studies include those of Hsu B et al. (International Journal of Neuropharmacology 1964; 2:283-290).
The tranquilizing action of dl-THP has previously been considered to be related to the blocking of the DA receptor. However, previous studies have used the results of animal behavioral tests to determine receptor binding characteristics of dl-THP and its enantiomers rather than actual in vitro assays. Therefore prior studies have, as a result, been limited in their scope and the understanding of the action of dl-THP which they are able to provide.
The present invention succeeds in identifying a previously unsuggested binding partner for dl-THP, namely the BDZ (benzodiazepine) binding site of the GABAA receptor (the gamma-aminobutyric acid) receptor. The dl-THP-GABA receptor interaction competitively inhibits other GABA receptor-BDZ interactions and provides novel observations of therapeutic effects achieved with dl-THP. This new understanding of the interactions of dl-THP provides the opportunity for previously unsuggested therapeutic uses of dl-THP.
According to the present invention there is provided a method of manufacture of a composition (e.g. a medicament) for the treatment of CNS disorders, including the treatment of anxiety and seizures, the composition comprising dl-THP (or one or more of its related compounds) and a physiologically acceptable carrier. In particular the composition may be an anxiolytic, or anticonvulsant. Part uses include the treatment of status epilepticus and cerebral palsy, seizure and generalized anxiety disorder (GAD), and as an anticonvulsant and anesthetic premedication. This contrasts with its previously reported effects such as its sedative-tranquilizing effect.
Also provided is a method of treatment of a CNS disorder as defined above in a patient, comprising administering to said patient a therapeutically effective quantity of dl-THP.
Also provided is the use of dl-THP in a method of manufacture of a medicament for the treatment of a CNS disorder as defined above.